Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12951-021-00925-1
Keywords
Ferritin; Integrin alpha(2)beta(1); Transferrin receptor 1; Receptor-mediated transcytosis (RMT); Blood-brain barrier
Funding
- Ministry of Science and Technology of Taiwan [107-2314-B-182A-149-MY3]
- Chang Gung Memorial Hospital [CMRPG3K1451]
- National Health Research Institutes [NHRI-EX109-10502NI]
- National Taiwan University [108L7866, 109L7866, 110L7814]
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The study demonstrated that the integrin alpha 2 beta 1-targeting H-ferritin (2D-HFn) based drug delivery system significantly increased drug loading capacity and tumor targeting capability, showing promising results in inhibiting glioma progression. This innovative technique may have great potential for more accurate brain tumor targeting and precision treatment arrangements in translational medicine.
Background: Ferritin, the natural iron storage protein complex, self-assembles into a uniform cage-like structure. Human H-ferritin (HFn) has been shown to transverse the blood-brain barrier (BBB) by binding to transferrin receptor 1 (TfR1), which is abundant in endothelial cells and overexpressed in tumors, and enters cells via endocytosis. Ferritin is easily genetically modified with various functional molecules, justifying that it possesses great potential for development into a nanocarrier drug delivery system. Results: In this study, a unique integrin alpha 2 beta 1-targeting H-ferritin (2D-HFn)-based drug delivery system was developed that highlights the feasibility of receptor-mediated transcytosis (RMT) for glioma tumor treatment. The integrin targeting alpha 2 beta 1 specificity was validated by biolayer interferometry in real time monitoring and followed by cell binding, chemo-drug encapsulation stability studies. Compared with naive HFn, 2D-HFn dramatically elevated not only doxorubicin (DOX) drug loading capacity (up to 458 drug molecules/protein cage) but also tumor targeting capability after crossing BBB in an in vitro transcytosis assay (twofold) and an in vivo orthotopic glioma model. Most importantly, DOX-loaded 2D-HFn significantly suppressed subcutaneous and orthotopic U-87MG tumor progression; in particular, orthotopic glioma mice survived for more than 80 days. Conclusions: We believe that this versatile nanoparticle has established a proof-of-concept platform to enable more accurate brain tumor targeting and precision treatment arrangements. Additionally, this unique RMT based ferritin drug delivery technique would accelerate the clinical development of an innovative drug delivery strategy for central nervous system diseases with limited side effects in translational medicine.
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